FDG PET and Immunoscintigraphy with 99mTc-Labeled Antibody Fragments for Detection of the Recurrence of Colorectal Carcinoma

Petra Willkomm, Hans Bender, Michael Bangard, Pan Decker, Frank Gru¨nwald, and Hans-Ju¨rgen Biersack

Departments of Nuclear Medicine and Surgery, University of Bonn, Bonn, Germany

36% of patients; regional lymph node metastases are present The aim of this study was to compare FDG PET with a new in 39%, and distant metastases are present in 19%. The monoclonal antibody–based imaging agent that comprises an overall 5-y survival rate after resection is 55%–75%. After anti–carcinoembryonic antigen (CEA) monoclonal antibody FabЈ primary surgery, 30%–40% of patients with resectable fragment directly labeled with 99mTc. Methods: Twenty-eight tumors experience disease relapse within 3 y. patients who were previously treated for colorectal carcinoma Because early detection and management of recurrent and in whom recurrence was suspected were examined with FDG PET and immunoscintigraphy. The most common indica- disease is associated with improved survival, early detection tions were an elevation of serum CEA (13 patients), suggestive of potentially resectable metastases or tumor recurrence lesions documented by CT (9 patients), sonography (4 patients), leads to improved prognosis (2). Serum levels of carcinoem- and severe constipation (2 patients). Planar imaging and SPECT bryonic antigen (CEA) may be used to monitor the presence were performed 4–6 h after intravenous injection of the new of recurrences with a sensitivity of 59% and a specificity of imaging agent. Whole-body PET was performed 45–60 min after 84% but not to localize recurrent lesions (1). intravenous injection of FDG. The findings were confirmed by Multiple imaging methods (sonography, CT, MRI) are conventional diagnostic modalities, surgery, and histology. Results: Histology confirmed local tumor recurrence in 9 of 28 thus used in routine follow-up to detect tumor recurrence, patients. Clinical follow-up or CT confirmed the presence of liver but they have only limited diagnostic accuracy (3–6). metastases in 9 patients and lymph node involvement, lung Identification of a presacral mass by conventional imaging metastases, and bone metastases in 2 patients each. The new does not allow accurate differentiation between scar tissue, agent correctly detected 8 of 9 local recurrences, whereas FDG fibrotic tissue, or tumor recurrence. Therefore, complemen- PET was able to detect all 9 cases and in 1 case was false- tary methods are warranted. FDG PET and immunoscintigra- positive. Liver metastases were confirmed in 9 patients by FDG phy with 99mTc-labeled anti-CEA antigen-binding fragments PET but in only 1 patient by the new agent. Two cases with lymph node metastases and 2 cases with lung metastases were as topofunctional imaging modalities have both been found correctly identified by FDG PET, but none were detected by the suitable, and several groups have shown that FDG uptake new agent. Finally, bone metastases were identified in 1 patient increases in colon and rectal carcinomas (4–13). by FDG PET but not with the new agent, whereas bone marrow Because FDG uptake can be observed in malignant and infiltration (n ϭ 1) was diagnosed by both imaging modalities. inflammatory lesions (14), the use of more specific tracers Conclusion: These results indicate that FDG PET and 99mTc- such as antibodies seems desirable. Many studies have used Ј labeled anti-CEA Fab are suitable for the diagnosis of local monoclonal antibodies to detect colorectal cancer (15–35). recurrence of colorectal carcinoma but that FDG PET is clearly Ј superior in the detection of distant metastases (liver, bone, and Recently, an (Fab ) antibody fragment specific to CEA that 99m lung) and lymph node involvement. can be labeled with Tc (CEA-Scan; Immunomedics, Inc., Key Words: colorectal cancer; monoclonal antibody FabЈ frag- Morris Plains, NJ) has become commercially available. ments; immunoscintigraphy; FDG PET Thus, specific images with good contrast between tumors J Nucl Med 2000; 41:1657–1663 and normal tissue can be expected (12,29,35). Our aim was to compare the efficacy of FDG PET with that of a 99mTc-labeled anti-CEA monoclonal antibody for the detec- tion of tumor recurrence and systemic spread of colorectal Colorectal cancer, the second leading cause of cancer carcinoma. mortality in the United States (1), has an incidence of MATERIALS AND METHODS approximately 12%–13% and a mortality rate of 10%–11%. At the time of first diagnosis, the disease is localized in only Patients Twenty-eight patients with suspected recurrence of colorectal carcinoma were enrolled and followed up for 6–19 mo. All were Received Sep. 27, 1999; revision accepted Mar. 8, 2000. For correspondence or reprints contact: Petra Willkomm, MD, Department of informed about the nature of the study and had given written Nuclear Medicine, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany. informed consent before the start of immunoscintigraphy or PET.

NEW IMAGING AGENT IN COLORECTAL CANCER • Willkomm et al. 1657 TABLE 1 Results for All Patients

Local Liver Distant recurrence metastases metastases Patient Age TNM CEA Indications no. Sex (y) Location classification level PET IS PET IS PET IS for study

1 F 57 R pT3 N0 M0 32 TP TP TN TN TN TN CT lesion behind bladder 2 M 54 R pT3 N1 M0 11 FP TN TP FN TN TN CT liver lesion 3 F 37 R pT2 N0 M0 9, 1 TN TN TN TN TN TN CEA level elevation 4 M 34 C.a. pT3 N3 M0 31 TN TN TN TN TP FN CEA level elevation 5 F 63 C.a. pT3 N2 M0 135 TN TN TP FN TN TN CEA level elevation 6 F 69 R pT3 N0 M0 15, 2 TN TN TN TN TN TN CT lesion after radiation 7 M 45 R pT1 N1 M0 365 TN TN TN TN TP TP CEA level elevation 8 M 68 R pT3 N0 M0 NA TP TP TN TN TN TN CT lesion behind bladder 9 F 62 R pT3 N0 M0 3, 4 TN TN TN TN TN TN Suggestive rectal sonog- raphy findings 10 M 70 S pT2 N0 M0 26 TP TP TN TN TN TN CEA level elevation 11 M 58 R pT3 N0 M1 19, 3 TN TN TP FN TN TN CEA level elevation 12 M 78 R pT3 N0 M1 24 TN TN TP FN TN TN CEA level elevation 13 M 65 S pT3 N2 M0 1, 4 TP FN TN TN TN TN Suggestive rectal sonog- raphy findings 14 F 69 R pT2 N0 M0 19 TN TN TN TN TN TN CEA elevation 15 F 71 R pT3 N0 Mx 15 TN TN TP FN TP FN CEA elevation 16 M 71 R pT3 N1 M1 1, 7 TN TN TN TN TN TN CT lesion behind bladder 17 M 61 S pT2 N0 Mx 1, 3 TN TN TN TN TN TN CT liver lesion 18 F 68 R pT3 N0 M0 6, 5 TN TN TN TN TP FN CT lung lesion 19 F 66 R pT4 N3 M0 5, 9 TP TP TP TP TN TN Suggestive sonography findings 20 M 50 R pT2 N0 Mx 1, 9 TN TN TN TN TN TN Constipation 21 M 51 R pT3 N0 Mx NA TP TP TN TN TN TN Constipation 22 F 68 R pT3 N0 Mx 25 TP TP TN TN TN TN CEA elevation 23 F 48 R pT2 N0 M0 13 TP TP TN TN TN TN CEA elevation 24 M 71 S pT3 N0 Mx 36 TN TN TP FN TN TN CEA elevation 25 F 67 R pT2 N0 M0 3, 4 TN TN TP FN TN TN CT liver lesion 26 M 71 R pT3 N1 Mx 1, 7 TN TN TN TN TN TN CT liver lesion 27 F 73 R pT3 N1 Mx 8 TN TN TP FN TN TN CEA level elevation 28 M 76 R pT3 N0 Mx 2, 4 TP TP TN TN TN TN Suggestive rectal sonog- raphy findings

TNM ϭ tumor node metastasis; IS ϭ immunoscintigraphy; R ϭ rectum; TP ϭ true-positive; TN ϭ true-negative; FP ϭ false-positive; FN ϭ false-negative; C.a. ϭ colon ascendens; NA ϭ not available; S ϭ sigma.

Immunoscintigraphy MBq 99mTc anti-CEA antibodies. The study consisted of planar CEA-Scan from a commercially available kit was labeled with images (500,000 counts) of the chest, abdomen, and pelvis in 99mTc according to the manufacturer’s guidelines. Images were anterior and posterior views after bladder voiding. Additionally, obtained with a double-head camera (Prism 2000; Picker Interna- SPECT of the pelvis was performed (3 degrees, 30 s per step, tional, Cleveland, OH) 4–6 h after intravenous injection of 740 step-and-shoot mode, 180° field of view); in 15 patients, SPECT of

TABLE 2 Number of Lesions Detected

PET/CEA-Scan Finding TP/TP TP/FN TN/FP TN/TN FP/FP FP/TN FN/TP FN/FN

Local recurrence 8 1 0 18 0 1 0 0 Liver metastases 1 8 0 19 0 0 0 0 Bone metastases 1 1 0 26 0 0 0 0 Lung metastases 0 2 0 26 0 0 0 0 Lymph node metastases 0 2 0 26 0 0 0 0

TP ϭ true-positive; TN ϭ true-negative; FP ϭ false-positive; FN ϭ false-negative. CEA-Scan is manufactured by Immunomedics, Inc.

1658 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 41 • No. 10 • October 2000 the liver was also performed. The data were processed with Local Recurrence Butterworth-filtered backprojection. CEA-Scan was able to correctly detect 8 of 9 cases of FDG PET local recurrence. In 1 patient, the findings were false- FDG was commercially obtained (Forschungszentrum Karls- negative. FDG PET showed intense uptake in 9 patients ruhe, Karlsruhe, Germany). Whole-body studies were performed (Fig. 1). One patient showed moderate uptake, which was using a dedicated PET scanner (ECAT EXACT; Siemens/CTI, identified as false-positive. Direct comparison with CEA- Knoxville, TN). Patients fasted overnight to reduce serum insulin Scan showed no uptake of monoclonal antibody (true- levels. Approximately 250–370 MBq FDG were injected intrave- nously and flushed with 20 mL saline solution. Patients were rested negative) in this FDG-positive lesion. at the time of injection and during the waiting period and were asked to drink 1 L water to promote diuresis. The bladder was voided before the examination to reduce artifacts. Scanning was initiated from the inguinal region to minimize bladder activity. Emission scans were obtained 45–60 min after the injection. For attenuation correction, measured transmission scans (7 min per bed position) were used. Tomograms were reconstructed by filtered backprojection with a Hanning filter (cutoff frequency, 0.4/cycle; decay correction; no scatter correction). Qualitative assessment of image quality comparing hot (patient not moved) and cold (patient moved between transmission and emission scans) transmission scans did not reveal significant differences. Image Assessment Primary image assessment was by 2 experienced nuclear medicine physicians unaware of the results of the other imaging studies. CEA-Scan findings were considered positive (tumor present) if the observers saw focal enhanced antibody uptake that could not be associated with physiologic accumulation (liver, kidneys, or bladder). FDG PET findings were classified as ‘‘malig- nancy—typical’’ when antibody uptake was markedly higher than liver uptake. Antibody uptake comparable to liver or mediastinum uptake was classified as ‘‘malignancy—suspect or inflammatory.’’ Antibody uptake lower than liver uptake but higher than back- ground activity was classified as ‘‘unspecific.’’ Absence of uptake in documented morphologic lesions was classified as ‘‘no evidence of disease.’’ After the primary assessment, all results were com- pared with the results of conventional imaging modalities.

RESULTS We investigated 28 patients (15 men, 13 women; median age, 62 y) with suspected recurrence who underwent resec- tion of colorectal cancer 6–52 mo previously (Table 1). The indications of recurrence were an increase in serum CEA (13 patients), CT-documented lesions (9 patients), constipation (2 patients), and sonographically documented lesions (4 patients). All patients underwent both imaging techniques within 6 d. The findings was corroborated surgically for 14 patients. The final institutional diagnosis, based on histology and clinical or radiologic follow-up, was used as the gold standard. Overall, recurrence of colorectal carcinoma was finally confirmed in 9 patients. Malignancy could be ruled out by clinical follow-up in 7 patients. Only local recurrence was detected in 7 patients; only metastases were found in 7 patients; and both recurrence and metastases were detected in 1 patient. Liver metastases were confirmed in 9 patients, FIGURE 1. (A) FDG PET image (sagittal view) shows large area (arrow) with intense FDG accumulation behind bladder. (B) and bone metastases, lung metastases, and lymph node CEA-Scan (Immunomedics) image of same patient shows in- metastases were confirmed in 2 patients each. Table 2 shows creased tracer accumulation in same area (arrow). Histologically, an analysis by tumor site. this area represented local recurrence.

NEW IMAGING AGENT IN COLORECTAL CANCER • Willkomm et al. 1659 Liver Metastases data show that local recurrence of colorectal carcinoma can All liver metastases were correctly confirmed by FDG be detected by both imaging modalities with high sensitivity PET (n ϭ 9), but in only 1 patient were liver metastases and specificity. correctly confirmed by CEA-Scan (Fig. 2). In CEA-Scan An initial report on the value of FDG PET in patients with images, large metastases appeared either scintigraphically suspected recurrent colorectal cancer by Schlag et al. (4) isointense in comparison with normal liver tissue or, in 1 showed intense FDG uptake in 11 of 12 patients with patient, as a cold lesion. confirmed recurrence. Ito et al. (9) and Schiepers et al. (13) Other Distant Metastases confirmed these results and observed a higher sensitivity and Two lymph node metastases and 2 cases of lung metasta- specificity for PET than for MRI. FDG PET was able to ses were correctly identified by FDG PET but were not differentiate scar tissue from tumor recurrence. Ogunbiyi et detected by CEA-Scan. Bone metastases were identified in 1 al. (36) investigated 58 patients with CT and FDG PET and of 2 patients by both imaging modalities and in 1 patient by found a specificity of 91% and a sensitivity of 100% for only FDG PET. FDG PET. Our results confirm their observation of increased Overall, with respect to local recurrence, CEA-Scan uptake of FDG in recurrent rectal cancer. In only 1 patient showed a sensitivity, specificity, and accuracy of 89%, (patient 2) were the findings misclassified as positive. 100%, and 96%, respectively. The sensitivity of FDG PET Problems with interpretation can occur because FDG is with regard to local recurrence was 100%, the specificity excreted by renal elimination and because some artifacts in was 95%, and the accuracy was 96% (Table 3). image reconstruction can be seen next to the kidney and urinary bladder, obscuring lesions or causing false-positive DISCUSSION findings. Because of this activity in the bladder, the dorsal We assessed the usefulness of CEA-Scan versus FDG pelvic region could not be fully analyzed. The study was PET in the detection of recurrent colorectal carcinoma. Our repeated with a bladder catheter and showed 1 hot spot,

FIGURE 2. (A) In upper abdomen, FDG PET images (coronal, transversal, and sagittal views) show focally enhanced glucose metabolism with central defect. In lower abdomen directly above bladder, coronal view shows circular lesion with enhanced glucose metabolism in outer rim and central defect. Arrowheads point to local recurrence of liver metastases. (B) Liver SPECT study (CEA-Scan; Immunomedics) reveals similar result, with tracer uptake in viable tumor mass (arrowhead). High uptake is also seen in normal liver and myocardium. (C) High uptake is seen in abdomen, similar to FDG PET. Arrowhead points to local recurrence.

1660 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 41 • No. 10 • October 2000 TABLE 3 seen in the urinary tract, gallbladder, and gastrointestinal Local Recurrence tract, especially in delayed images, and can lead to misdiag- noses. Bowel preparation with an iso-osmotic solution and CEA-Scan FDG PET Index (%) (%) intravenous application of furosemide are possible methods for overcoming this disadvantage. In our patient with Sensitivity 89 100 false-negative findings, pathologic monoclonal antibody Specificity 100 95 Positive predictive value 100 90 accumulation was missed, probably because of small tumor Negative predictive value 95 100 size (Ͻ2 cm). Accuracy 96 96 If the results of FDG PET are compared with those of CEA-Scan, we find that both imaging modalities are sensi- CEA-Scan is manufactured by Immunomedics, Inc. tive in detecting local recurrence. Although image quality (resolution and contrast between tumor and normal tissue) was clearly better for FDG PET than for CEA-Scan, the which was classified as tumor recurrence, in the dorsal part actual benefit was only marginal. of the pelvic area. The patient was followed up by several A second goal was to evaluate the possibility of restaging CT examinations over 9 mo, with no sign of morphologic with both methods. Some authors report that FDG PET is changes. Thus, we assume that the retained activity was more sensitive than CT in the clinical assessment of patients caused by persisting urinary activity, an observation that with metastatic colorectal cancer. Lai et al. (39) reported that Miraldi et al. (37) reported. FDG PET showed better results in detecting extrahepatic Major objections to FDG PET have been based mainly on lesions than did conventional imaging. Ogunbiyi et al. (36) the assumption that FDG may be too unspecific a tracer, reported that FDG PET was 95%–100% sensitive for because false-positive findings may occur in inflammatory detecting liver metastases. These values were superior to disease (14,38). Because FDG PET is commonly expensive, those for CT, which had a sensitivity of 74% and a its use is limited and other techniques are warranted. specificity of 85%. Another group (40) found a sensitivity of Therefore, we compared our results with the findings for 100% and a specificity of 67% for restaging colorectal CEA-Scan, which is a new 99mTc-labeled antibody (FabЈ) carcinoma. Our data show that tumor spread with lymph fragment specific to CEA. Eight of 9 cases were confirmed node, liver, and lung metastases was accurately detected by correctly by CEA-Scan. Because other investigators have FDG PET. However, with 1 exception, CEA-Scan failed to observed similar results using CEA-Scan (22,24,25,27– reveal these tumor sites because of insufficient monoclonal 29,35), this agent seems to be useful for establishing local antibody accumulation in these patients. Behr et al. (29) tumor recurrence. Our data show that CEA-Scan is helpful observed a similar result using an intact anti-CEA immuno- in detecting disease recurrence after surgical resection of globulin G. They also described diminished tumor-to-liver primary colorectal cancer. In accordance with studies by ratios in large liver metastases when fragments were used. Behr et al. (31), our study also showed that CEA-Scan can Fragments have been shown to exert higher tumor-to- disclose serum CEA-negative tumor recurrence and high background ratios, rather because of significant enhanced circulating CEA titers. background clearance than because of enhanced absolute Nevertheless, the evaluation of such malignancies is uptake. In addition, the imaging characteristics of 99mTc- complicated, as shown by our patient with false-negative labeled antibodies are preferential (higher application dose, findings. Physiologic excretion of monoclonal antibody is better detection sensitivities, use of SPECT). In our study,

TABLE 4 Scintigraphic Results for Liver Metastases

FDG Liver Metastatic Type of PET CEA-Scan SPECT tumor size confirmation Comments

TP FN Yes 1 cm Histologic TP FN Yes 3 cm Radiologic No resection, multiple liver metastases TP FN Yes 2 cm Histologic TP FN Yes 5 cm Histologic No resection, multiple liver metastases TP FN No 1 and 5 cm Radiologic No resection, multiple liver metastases TP TP Yes 12 cm Histologic TP FN No 4 cm Radiologic No resection, multiple liver metastases TP FN No 2 cm Histologic TP FN No 3 cm Radiologic No resection

TP ϭ true-positive; FN ϭ false-negative. CEA-Scan is manufactured by Immunomedics, Inc.

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